1. Field of the Invention
This invention relates to a pharmaceutical preparation in pressure-sensitive adhesive tape form that permits the percutaneous absorption of nitroglycerin over a long period of time at a controlled rate.
2. Description of the Prior Art
Nitroglycerin is used as a medicine for the treatment and for the prevention of heart disease such as angina pectoris, myocardial infarction, cardiac insufficiency, and the like. When nitroglycerin is administered by, for example, intravenous injection, its effects are lost after a very short period of time. Also, because the nitroglycerin in the blood is thereby raised to a high level for a short period of time, there are the disadvantages of side effects such as headache, dizziness, orthostatic hypotension, etc. In order to keep the blood level of nitroglycerin at a fixed value for relatively long periods of time, a preparation that has a layer of adhesive that contains nitroglycerin on a backing can be used, and the nitroglycerin can be absorbed percutaneously. The drug nitroglycerin is relatively easily absorbed through the skin. For that reason, if adhesives such as natural rubber, polyisobutyrene, silicone resin, etc., in which nitroglycerin is relatively insoluble are used, the skin-adhesive partition coefficient of nitroglycerin is high, and the permeation rate through the skin is therefore too high, resulting in the side effects mentioned above. In order to achieve the effective use of the pharmacological effects of nitroglycerin, continuous percutaneous absorption by which a blood level of nitroglycerin of 0.05-2.0 ng/ml is maintained is preferable. For this purpose, a number of steps have been taken, such as the selection of an adhesive base by which the rate of percutaneous absorption of the nitroglycerin can be controlled.
Preparations of nitroglycerin comprising adhesive bases that can control the release of nitroglycerin more readily than those mentioned above have been disclosed in, for example, Japanese Laid-Open Patent Publications 56-133381, 57-77617, 55-2604, and 63-246325 which corresponds to U.S. Pat. No. 4,971,799. For example, Japanese Laid-Open Patent Publication 57-77617 discloses a preparation containing a copolymer as an adhesive base that can be obtained by the copolymerization of dodecyl methacrylate, a functional monomer such as acrylic acid, and a specific alkyl (meth)acrylate, and the like. The preparation of nitroglycerin is prepared by dissolving the adhesive base into an appropriate organic solvent, coating the resulting solution on a backing to form an adhesive layer, and then drying the adhesive layer. However, because a large amount of monomers that can form a relatively softer copolymer, e.g., dodecyl methacrylate, are used in the copolymerization process, the resulting copolymer does not have sufficient cohesive strength. For that reason, it is difficult to add nitroglycerin to the adhesive layer in high concentrations. In order to administer a fixed amount of nitroglycerin, it is necessary to use a large surface area of the preparation, which makes a patient uncomfortable due to irritation.
Japanese Laid-Open Patent Publication 63-246325 which corresponds to U.S. Pat. No. 4,971,799 discloses preparations of nitroglycerin containing as an adhesive base a copolymer of specific alkyl (meth)acrylates in an adhesive layer. The number of carbons in the alkyl groups of the alkyl (meth)acrylate is 6 or more. The copolymer contains 2-ethylhexyl methacrylate as a copolymer component in the concentration of 40-90% by weight, and has a rolling ball tack value of 2 or less. The adhesive layer can contain nitroglycerin in relatively high concentrations. However, when a large amount of nitroglycerin is contained in the adhesive layer, the adhesive layer will soften, and consequently, adhesiveness to the surface of the skin is not sufficient. In other words, a preparation with sufficient adhesiveness of this type of preparation cannot release a sufficient amount of nitroglycerin.
Moreover, preparations of nitroglycerin which is produced by the impregnation method are known. In this method, first, an adhesive layer that does not contain any drug is formed on a backing, and a soft ointment or the like containing nitroglycerin is applied to this adhesive layer and left to mature so that nitroglycerin is transferred to the adhesive layer. However, in this impregnation method, it is difficult to obtain an adhesive base in which the nitroglycerin is distributed uniformly at a high concentration. In this way, the preparation that is obtained by the impregnation method has a small amount of nitroglycerin in the adhesive base, so that long pharmacological term effectiveness is not achieved. Moreover, the amount of nitroglycerin per unit of surface area is small, and it is necessary to use a large surface area of the preparation in order to administer a suffient amount of nitroglycerin.
Japanese National Publications 61-502760 and 62-502965 disclose preparations containing nitroglycerin in high concentrations (about 20 to 60% by weight) in acrylic-type adhesive bases to improve the rate of release of the nitroglycerin. However, the presence of nitroglycerin in high concentrations in the adhesive base of these preparations may be in danger of explosion. Also, in order that a large amount of nitroglycerin can be contained in the adhesive base, polar groups are introduced into the adhesive base polymer, or the adhesive base polymer is crosslinked so that the cohesive strength of the adhesive base is improved. However, the following problems arise. For example, the adhesive base polymer is crosslinked by a chemical reaction after the addition of nitroglycerin in Japanese National Publication 61-502760 mentioned above. The crosslinking reaction causes the nitroglycerin to decompose, resulting in the accumulation of the decomposed products. Also, it is difficult to complete the crosslinking reaction described above, and the unreacted active groups will remain in the adhesive base. These decomposed products and unreacted active groups may irritate the skin. Moreover, there is another problem that when the adhesive base is treated as described above to improve its cohesive strength, the release of the nitroglycerin will be reduced. To solve this problem, auxiliary absorbents are used to increase the release of nitroglycerin in Japanese National Publication 62-502965 mentioned above. However, because the auxiliary absorbents with interfacial activity generally irritate the skin, they are not preferred for use as a component of the preparation.
Additionally, preparations that can control the percutaneous absorption of nitroglycerin in other manners than the selection of an adhesive base have been proposed. For example, Japanese Patent Publication 54-16566 discloses a preparation of nitroglycerin obtained by forming a storage layer containing nitroglycerin in a high concentration on a backing, and then layering a membrane with micro-pores, for a controlled release and an adhesive layer in this order thereon. Japanese Laid-Open Patent Publications 55-94316, 57-14522, and 57-59806, and Japanese National Publication 57-500831 disclose preparations composed of two layers, a base layer of non-adhesive resin such as polyvinyl alcohol containing nitroglycerin therein, and an adhesive layer disposed on the base layer, by which the base layer is allowed to adhere to the skin surface. Japanese Laid-Open Patent Publication 59-207149 and 56-125311 disclose preparations obtained by layering two or more base layers containing different concentrations of nitroglycerin on a backing, and then layering an adhesive layer thereon. Also, a preparation that has an adhesive layer containing microencapsulated nitroglycerin particles that were obtained by encapsulating nitroglycerin particles by a micro-pore film has been proposed. However, the manufacture of all of these preparations is complicated, which makes it difficult in to obtain a preparation that contains nitroglycerin at low cost.